Fluid status is an important issue in long-term dialysis patients and is related to clinical outcome. In fact, knowledge of a patient's fluid status is essential in efficiently managing hemo- as well as peritoneal-dialysis patients. Chronic fluid overload is associated with left ventricular hypertrophy, left ventricular dilatation, arterial hypertension, and eventually the development of congestive heart failure. High interdialytic weight gain on top of chronic fluid overload further increases the burden for the cardiovascular system. Recent studies have shown that fluid overload can even be linked to an increased mortality (Wizemann V. et al., “The mortality risk of overhydration in haemodialysis patients”, Nephrol. Dial. Transplant 2009, 24:1574-1579). Management of the fluid status involves restriction of sodium intake and, to the extent possible and over time, attainment of a post-dialysis weight equal to the patient's dry weight or normohydration weight.
Normohydration weight is defined as the weight the patient would have with zero fluid overload. Fluid overload can be expressed as excess extracellular fluid volume (ECV). In order to have a comparative standard for a reference to body mass, body composition or total body water (TBW) is required.
In comparison, dry weight may be defined as the weight at which an individual is as close as possible to a normal fluid status without experiencing symptoms indicative of fluid overload or deficit. Clinically, dry weight is determined as the lowest weight a patient can tolerate without developing intra- or interdialytic symptoms of hypovolemia. This clinical assessment is hampered by the fact that some liters of fluid may accumulate in the body before an oedema becomes clinically evident and that it does not account for changes in lean body mass, fat mass or nutritional status over time. In addition, some patients may have symptoms on dialysis for heart problems that may not be related to fluid overload.
Therefore, normohydration and dry weight are closely linked with dry weight being slightly less than normohydration weight.
Several methods of determining the fluid status of an individual exist:
Isotope dilution methods are frequently recommended for fluid volume measurement (ECV or TBW), but they are clinically not feasible because of complexity and expense. Furthermore, these methods can determine the absolute quantities of ECV and TBW but cannot determine the amount of excess extracellular water (fluid overload) and thus no value for the normohydration weight.
Efforts have been made in the past to use the bioimpedance technology to facilitate the fluid reduction process. Cf., for example, Kuhlmann et al., “Bioimpedance, dry weight and blood pressure control: new methods and consequences”, Current Opinion in Nephrology and Hypertension, 2005, 14:543-549, the disclosure of which is entirely incorporated by reference.
Several different bioimpedance approaches to determine the optimal fluid status have been published:
The normovolemic-hypervolemic slope method, cf., e.g. Chamney et al., “A new technique for establishing dry weight in hemodialysis patients via whole body bioimpedance”, Kidney Int., 2002, 61:2250-2258, the disclosure of which is entirely incorporated by reference, applies whole body multi-frequency bioimpedance to assess pre-dialytic total body extracellular fluid volume and compares the extracellular fluid volume/body weight relation at hypervolemia with the standard value in normovolemic individuals.
The resistance-reactance graph method, cf., e.g. Piccoli et al., “A new method for monitoring body fluid variation by bioimpedance analysis: the RXc graph”, Kidney Int., 1994, 46:534-539, the disclosure of which is entirely incorporated by reference, uses whole body single frequency bioimpedance for assessment of fluid status and nutritional status from height-adjusted resistance and reactance. The resulting resistance-reactance vector is set in relation to a distribution range in a normovolemic population. The difficulty of this method is that it does not provide absolute values of the fluid status—patients can only be compared to percentiles of a normal population.
Whole body bioimpedance spectroscopy (wBIS) is a noninvasive technique calculating the “whole body” extracellular fluid volume (wECV) and the whole body intracellular fluid volume (wICV) by measuring resistance and reactance over a range of alternating current frequencies (e.g. 50 to 250 frequencies from ca. 1 kHz to 1000 kHz). Ratios of wECV or wICV to total body water volume (TBW) or the ratio wECV/wICV are used to assess the fluid status of a patient, cf., e.g. Wei Chen et al., “Extracellular Water/Intracellular Water Is a Strong Predictor of Patient Survival in Incident Peritoneal Dialysis Patients”, Blood Purif., 2007, 25:260-266, the disclosure of which is entirely incorporated by reference.
The newest and more sophisticated technique is a whole body bioimpedance spectroscopy with a physiological tissue model: wECV and wTBW are measured by whole body bioimpedance spectroscopy and additionally the fluid status and body composition are calculated. This is achieved by setting the measured patient in relation to a subject with a normal fluid status and the same body composition. Thus it relates back to the normohydrated properties of tissue. This physiologic tissue model is described in “A whole-body model to distinguish excess fluid from the hydration of major body tissues”, Chamney P. W., Wabel P., Moissl U. M. et al., Am. J. Clin. Nutr., 2007, January, 85(1):80-9, the disclosure of which is entirely incorporated by reference. This method allows the patient specific prediction of the normal fluid status and the normal fluid status weight—the weight, the patient would have with a working kidney. This method also allows to determine the composition of the individual including adipose tissue mass (ATM or MAT), lean tissue mass (LTM or MLT) and extracellular water volume ECW.
An alternative method (see, for example, Zhu et al., “Adjustment of dry weight in hemodialysis patients using intradialytic continuous multifrequency bioimpedance of the calf”, Int. J. Artif. Organs, 2004, 12:104-109 and Zhu et al., “A method for the estimation of hydration state during hemodialysis using a calf bioimpedance technique”, Physiol. Meas., 2008: S503-S516, the disclosures of which are entirely incorporated by reference) uses segmental bioimpedance in the form of continuous intradialytic calf bioimpedance to record changes in calf extracellular volume during dialysis. Normohydration weight determined by this method is defined as the body weight at which calf extracellular volume is not further reduced despite ongoing ultrafiltration. Although this method is good for estimating normohydration of a patient, the technique requires the performance of bioimpedance measurements throughout a dialysis session. In fact, a prediction of the normohydration weight is not feasible at all. In addition, patient movement at the lower limb is limited during the dialysis session and measuring electrodes have to be kept in place until the session is finished.
Fluid management of individuals undergoing dialysis and/or ultrafiltration comprises three main steps: 1) the assessment of fluid status, 2) the optimisation of fluid status towards normohydration and 3) the maintenance of an “optimized” normohydration fluid status corresponding to the normohydration weight.
The above described methods cover the first step, and using a fluid reduction protocol as described in Petr Machek et. al.: “Guided optimization of fluid status in haemodialysis patients”, Nephrol Dial Transplant (2010) 25: 538-544, which is incorporated by reference in its entirety provides a solution for the second step. Nevertheless, an urgent need exists to find a solution for maintaining the optimal fluid status.
This is particularly tricky, since one has to detect if an individual's weight alternates due to a change of fluid overload or due to a change in normohydration weight because of a change in bodycomposition (lean or fat mass).
Changes in normohydration weight can occur very quickly and may be overlooked in a lot of cases, leading to subsequent over- or underhydration over a longer period of time if the dialysis postweight, i.e. the weight after a dialysis, is not adjusted.
Therefore, either the fluid status and/or the normohydration weight should be updated regularly, at best in every treatment.
Unfortunately, the above described bioimpedance methods cannot be used in every treatment, but rather on a monthly basis or even just once every three months, in particular due to costs and/or to discomfort that these methods cause to the monitored individual.
Various other approaches to detect a change in the fluid status have been developed, such as blood volume monitoring, ultrasound assessment of inferior vena cava diameter and several biochemical parameters, such as brain or atrial natriuretic peptide.
In particular blood volume monitoring or plasma volume monitoring is believed to be a good indicator for detecting a change of fluid status or even to determine dry weight of an individual, cf., e.g. A. D. Sinha et al.: “Relative Plasma Volume Monitoring During Hemodialysis Aids the Assessment of Dry Weight”, Hypertension. 2010; 55: 305-311, the disclosure of which is entirely incorporated by reference. Plasma volume monitoring assesses the balance between refilling and ultrafiltration rate in respect to the absolute plasma volume. Fluid overload is one of many factors influencing this relationship. Plasma is thereby directly linked to blood volume. Relative blood volume is a ratio of the blood volume at a certain moment compared to an earlier determined blood volume, e.g. at the beginning of a treatment session.
It has often been reported that flat relative blood volume curves are a sign of excessive fluid overload. According to Guyton, about ⅔ of fluid overload contribute to the interstitial space, and the remaining ⅓ contributes to the plasma volume, c.f. Guyton A. C. et al., “JE. Textbook of Medical Physiology”, Philadelphia, W.B. Saunders, 2000, the disclosure of which is entirely incorporated by reference. Both effects result in a flatter relative blood volume curve: firstly, interstitial fluid overload provides a fluid reservoir that facilitates refilling from the interstitial to the vascular space. Secondly, a 1 L decrease in plasma volume will lead to a smaller relative change if the absolute plasma volume is higher.
None of these approaches, however, give an accurate estimate of the change of fluid status (overload/normohydration) due to the fact that they have not been proven to be practical or reliable in the determination in individual patients. Consequently, a majority of dialysis patients may be fluid overloaded or depleted without specific symptoms.
Therefore, there exists an urgent need to find an applicable parameter which can be determined cost-efficiently, easily and regularly without causing discomfort or even distress to the patient.
Furthermore, an urgent need for a determination of a change in fluid status and/or a fluid status and a treatment of an individual based on such a parameter exists, in particular to avoid unnoticed fluid overload or depletion in treated individuals. Put simply, it would be beneficial for the adequate fluid management of individuals to quantify fluid overload or even to be able to estimate dry weight and/or normohydration weight more reliably without causing discomfort to the individual than currently done in clinical practice.